Telomeres are essential for chromosome stability. In the absence of telomere function chromosomes fuse and undergo other rearrangements and chromosome loss occurs. Evidence over the past seven years has suggested that maintenance of telomere length plays an important role in tumor progression and tumor growth. To probe the role of telomeres in normal cells and in tumor swe generated a telomerase null mouse in collaboration with Dr. Ronald DePinho's. Telomerase is a unique enzyme, requiring both a reverse transcriptase-like protein and a RNA component that synthesizes telomeres sequences onto chromosome ends. In the absence of telomerase, telomeres shorten progressively and telomere functions is lost after a number of cell divisions. The telomerase null mouse shows a progressive decrease in fertility and viability over six mouse generations. In the later generation, loss of cell viability is most apparent in highly proliferative organ systems. The loss of telomere function in late generation animal allows to study the fundamental consequences of the loss of telomere function in mammalian cells. In this application, we will address the role of checkpoint functions in loss of cell viability and probe the mechanisms that lead to chromosomal rearrangements. Our recent collaborative studies demonstrated that, in addition to a role in tumor growth, the absence of telomerase may lead to increased genetic instability and increased tumor formation. Thus the outcome of telomerase inhibition depends on the genetic background of the cell. Since telomerase inhibition is being pursued as an anti-cancer strategy, it is essential to understand in detail the consequence of telomerase inhibition in a variety of settings. In this application we propose to continue crosses of the telomerase null mouse to a variety of tumor prone mice to further explore the role of telomere function in tumor growth.